The Role of Recycling Immune Complexes in the Breakdown of Tolerance

描述(申请人提供)：在系统性红斑狼疮(SLE)中，有缺陷的细胞凋亡清除和循环免疫复合体(ICs)的增加已多次被认为与细胞因子的分泌增加有关。尽管存在清除缺陷的证据，而且推测TLR配体对内体的访问减少，但已发现细胞因子的分泌是由激活的内体TLR引起的。这一悖论提出了一种更复杂的模型，涉及TLR依赖和非TLR依赖的机制来调节细胞因子的分泌。我们的初步数据显示，部分通过Fc？RS结合的Ig G-ICs(Ig G-APOP Ics)在有自身免疫倾向的MRL/LPR小鼠的DC和MFS表面增加了30倍。我们表明，这种积累是由于降解缺陷促进了内化的Fc？RS结合的Ig G-IC的循环。在体内和体外，ICs的积累增加了BAFF的分泌。在这一应用中，我们将检验中心假设，即由于内吞/吞噬途径中的ICs靶向或降解缺陷，Ig G-APOP ICs聚集在DC和MFS上。这导致了致病细胞因子的产生，这是遗传易感性和慢性TLR和/或Fc？RS信号的结果。我们在目标1中建议确定在降解途径中ICs的进展在哪里被减弱。在目标2中，我们假设当与FC？RS结合的IC在循环过程中保持聚集时，慢性FC？RS信号会导致，而当IC负载的FC？RS在这些通路中停留较长时间时，慢性TLR信号会导致慢性TLR信号。最后，我们认为，尽管遗传易感性可能是导致IC循环的缺陷的基础，但遗传事件也可能是细胞因子分泌增加所必需的。我们将通过在非自身免疫小鼠中通过药物诱导IC循环并评估这是否导致细胞因子产生增加来分离这些假定的遗传事件。总体而言，这一建议意义重大，因为它确定了IC积聚在DC和MFS上，并定义了一种更复杂的机制，说明TLR依赖和TLR非依赖机制如何导致狼疮相关细胞因子水平升高。

DESCRIPTION (provided by applicant): The defective clearance of apoptotic cells and the increase in circulating immune complexes (ICs) have repeatedly been implicated in heightened cytokine secretion in systemic lupus erythematosus (SLE). Despite evidence of clearance defects, and presumably diminished access of TLR ligands to the endosome, cytokine secretion has been found to result from activated endosomal TLRs. This paradox raised the possibility that a more complicated model involving TLR-dependent and TLR-independent mechanisms regulates cytokine secretion. Our preliminary data show that IgG-ICs (IgG-apop ICs) bound in part via Fc?Rs are elevated 30-fold on the surface of DCs and MFs from autoimmune prone MRL/lpr mice. We show that this accumulation results from a degradation defect that promotes the recycling of internalized Fc?Rs bound IgG-ICs. In vivo and in vitro, the accumulation of ICs heightens BAFF secretion. In this application we will test the central hypothesis that IgG-apop ICs accumulate on DCs and MFs due to defects in targeting or degrading ICs within the endocytic/phagocytic pathway. This leads to pathogenic cytokine production as a consequence of genetic predisposition and chronic TLR and/or Fc?Rs signaling. We propose in aim 1 to identify where in the degradative pathway the progression of ICs is attenuated. In aim 2, we postulate that chronic Fc?Rs signaling results when ICs bound to Fc?Rs remain aggregated during the recycling process, and that chronic TLR signaling results when the IC-loaded Fc?Rs spend prolonged time within these pathways. Lastly, we propose that although genetic predisposition might underlie the defects leading to the recycling of ICs, genetic events might also be required for heightened cytokine secretion. We will separate these putative genetic events by pharmacologically inducing IC recycling in non-autoimmune mice and assessing whether this leads to heightened cytokine production. Overall, this proposal is significant because it identifies that ICs accumulate on DCs and MFs and defines a more intricate mechanism for how TLR-dependent and TLR- independent mechanisms might contribute to elevated levels of lupus-related cytokines.